The tricyclic 6,7-dihydro[3,4-c]pyrido[2,3-d]pyrimidine ring system has been the subject of intensive studies because such ring system is structurally very close to the key skeleton of 5,10-methylenetetrahydrofolic acid which donates one carbon unit to 2'-deoxyuridylic acid to produce thymidylic acid during the de novo synthesis of DNA.
For normal or neoplastic cell growth or cell division, DNA must be synthesized. During the synthesis of DNA, folic acid is converted into its active form, 5,10-methylenetetrahydrofolic acid, which then methylate 2'-deoxyuridylate to produce thymidyate, a building block in the snythesis of DNA. Methotrexate and other folic acid analogues block the formation of 5,10-methylenetetrahydrofolic acid and thereby produce a "starvation" of thymidylate and an inhibition of DNA synthesis.
No successful synthesis of the tricyclic 6,7-dihydro[3,4-c]pyrido[2,3-dpyrimidine ring system has been reported. This invention deals with the first synthesis of the tricyclic derivatives by two different routes: one by construction of the pyrimidine ring on the 2,3-dihydropyrrolo[3,4-c]pyridine system and the other by addition of the 5-membered pyrrolidine ring to the preformed pyrido[2,3-d]pyrimidine ring system.
The derivatives of this invention may interfere with thymidylate synthesis from 2'-deoxyuridylate. Since the derivatives of the subject invention resemble structurally 5,10-methylenetetrahydrofolic acid, they may react with methylene tetrahydrofolate cyclase. The compounds of the subject invention may also react with 2'-deoxyuridylate in the active site of thymidylate synthase to form an enzyme substrate complex in which the complex can not release the product. Accordingly, the derivatives of the subject invention may be useful as biochemical probes for biological reactions essential for DNA synthesis.
The derivatives of this invention may also be useful as potential anticancer agents since they inhibit DNA synthesis at the thymidylate level. In the same manner as several folic acid analogues, such as methotrexate, 10-deaza-10-ethyl-methotrexate or aminopterin, the derivatives of the present invention may inhibit thymidylate formation and thus DNA synthesis.